This invention is generally in the field of drug delivery devices for the controlled release of small, water-soluble molecules. Particularly, the disclosed system is a polymeric composition useful for the controlled and continuous delivery of biologically active drugs from a non-erodible, hydrophobic polymer matrix device.
In recent years great efforts have been made to develop polymeric compositions which are capable of delivering active agents, particularly drugs, over extended periods of time in a controlled fashion. The purpose of these systems is to deliver such drugs at a predictable and predetermined rate to achieve a desired physiological or pharmacological effect. For example, see U.S. Pat. No. 4,391,797 to Folkman, et al.; U.S. Pat. No. 4,069,307, to Higuchi, et al.; and U.S. Pat. No. 3,948,254, to Zaffaroni.
A number of polymeric devices have been developed to control the release of low molecular weight (less than 1000) drugs. See, for example, A. C. Tanquary and R. E. Lacey, eds., Controlled Release of Biologically Active Agents, (Plenum, New York). In almost all cases, the mechanism of release is the diffusion of the drug through a solid polymer, and diffusion rates are generally low, as discussed by Siegel and Langer, Pharmaceutical Research, 1, 2-10 (1984). While the devices disclosed by the prior art possesses desirable release kinetics for a variety of low molecular weight substances with low or no water solubility, these devices are limited in that they do not release drugs with high water solubility for extended periods of time in a controlled, zero-order fashion. "Zero-order" is defined as a linear relationship between amount released and time of release.
The difficulty of obtaining zero-order release of water-soluble molecules for long time periods is apparent when one considers the release mechanism of drugs from polymeric matrix devices. Polymeric devices function by passive diffusion of the molecules either through the polymer itself, for low molecular weight molecules, or through a matrix of channels and pores, for macromolecules. Diffusion is not only dependent on factors such as drug loading, matrix coating or drug particle size, but is also greatly influenced by the water solubility and molecular weight of the drug embedded in the matrix, discussed by Rhine, et al., J. Pharmaceutical Sciences, 69(3), 265-270 (1980). Thus, molecules which are either very large, defined as molecules having molecular weights greater than 1000, or poorly water-soluble, will be retained in the matrix more readily and zero-order release kinetics will be more easily achieved. It is similarly apparent that drugs with good water solubility will diffuse readily and polymeric devices containing such drugs release the embedded drug relatively quickly, in a non-linear fashion, not with zero-order release kinetics for long time periods. Another factor which plays a major role is the nature of the polymer itself, i.e., biodegradable versus non-biodegradable, and the degradation kinetics.
As the following table shows, the prior art discloses sustained and/or controlled release of small molecules from polymeric devices, but the drugs being released were water insoluble or almost insoluble and of low molecular weight. The approximate molecular weight (m.w.) and solubility in water is taken from "The Merck Index, 10th Edition", (Merck & Co., Rahway, N.J., 1983).
TABLE 1 ______________________________________ Molecular weight and solubility of compounds released from prior art polymeric devices. Drug M.W. Solubility Reference ______________________________________ Progesterone 314 Insoluble Higuchi U.S. Pat. No. 4,069,307 Zaffaroni U.S. Pat. No. 3,948,254 Dick UK Pat. 2,167,662A Diethyl- 268 almost insoluble Higuchi stilbestrol U.S. Pat. No. 4,069,307 Estradiol 272 almost insoluble Zaffaroni U.S. Pat. No. 3,948,254 Dick UK Pat. 2,167,662A Medroxy- 341 insoluble Higuchi progesterone U.S. Pat. No. 4,069,307 Digoxin 781 almost insoluble Appelgren U.S. Pat. No. 4,263,273 Nandrolone 274 insoluble Dick UK Pat. 2,167,662A ______________________________________
In summary, the prior art discloses sustained or controlled-release of drugs of low molecular weight from polymeric devices, but such drugs were primarily molecules which were either insoluble or almost insoluble in water.
Another factor known to influence release kinetics of polymeric compositions is the molecular weight of the drug embedded into the matrix. The prior art discloses various devices to release macromolecules for an extended period of time. For example, W. D. Rhine et al., J. Pharmaceutical Science, 69(3), (1980) report a fabrication method that allows for the controlled release of serum albumin (M. W. of 68,000). It is noted, however, that linear release was only obtained when the drug loading of the polymeric device was below 37.5%. Also, U.S. Pat. No. 4,164,560 to Folkman discloses release of proteins from a polymeric device, where linear (zero-order) release was observed from day 40 to day 100, at which time the device was empty. Similarly, U.S. Pat. No. 4,675,189 to Kent, et al., reports release of a water soluble polypeptide (LH-RH, m.w. 1182.33), but release is merely sustained, not linear.
If one considers the length of time with which controlled drug delivery was obtained it becomes obvious that the length of time precludes the use of the various devices for a number of clinical applications. For example, if it is desired to treat chronic neurological disorders which affect the nervous system, such as Parkinson's disease, then long-term controlled linear release of clinically useful amounts of a therapeutic agent, such as L-DOPA, would be desirable. Such a device has not been available. The following table indicates the time of linearity, the total linear period as well as the references of the prior art devices.
TABLE 2 __________________________________________________________________________ Linearity of release of compounds from prior art polymeric devices. total linear First Time of linearity period Author/Inventor reference __________________________________________________________________________ hr. 6-12 6 hrs. Appelgren U.S. Pat. No. 4,263,273 hr. 1-4 3 hrs. Bloch U.S. Pat. No. 3,965,255 Days 56-105 51 days Dick UK Pat 2,167,662 Days 22-105 83 days Folkman U.S. Pat. No. 4,391,797 day 40-140 100 days Sidman U.S. Pat. No. 4,351,337 hrs. 20-70 50 hrs. Theeuwes U.S. Pat. No. 4,278,087 hrs. 4-11 7 hrs. Theeuwes U.S. Pat. No. 4,217,898 days 14-39 25 days Yolles U.S. Pat. No. 3,880,991 not provided not provided Higuchi U.S. Pat. No. 3,832,252 hrs. 36-180 6 days Michaels U.S. Pat. No. 4,177,256 hrs. 40-180 5.8 days Suzuki & Price J.Pharm.Sci. 74(1)(1985) __________________________________________________________________________
While these polymeric devices are useful for dispensing a number of agents, there may be instances where it would be desirable to provide a degree of control of release for small and water-soluble molecules which is greater than that provided by the prior art. For example, fluid, rapid, short-term release may not be desirable in situations involving release of an agent which is very water soluble. The prior art does not disclose a composition or method whereby water-soluble molecules that have a m.w. of less than 1000 can be released at a controlled, zero-order rate for any appreciable period of time.
U.S. Pat. No. 4,883,666 describes several examples in which dopamine and L-Dopa are released from ethylene vinyl acetate polymeric devices. In one example in U.S. Pat. No. 4,883,666, dopamine, a substance readily soluble in water, is very rapidly released at a non-linear rate when no coating surrounds the loaded polymer core. Linearity was only obtained when a nonpenetrable barrier was formed around the polymer core and a hole in the coating permitted the solution to have access to the loaded core of the device. The need to form a barrier around a loaded core greatly limits the use of such devices, largely because the absolute amount of drug that can be released from such a device is relatively small, generally insufficient for clinical use.
It is therefore an object of the present invention to provide a delivery device allowing long-term, linear release of small, less than 1000 m.w., water-soluble molecules, and method for use thereof.
Another object of the present invention is to provide a small polymeric device that can release a relatively large amount of low molecular weight, water soluble drug.